CDX2 expression in the hematopoietic lineage promotes leukemogenesis via TGFβ inhibition.
Fiche publication
Date publication
mai 2021
Journal
Molecular oncology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHENARD Marie-Pierre, Dr DOMON-DELL Claire, Dr DULUC Isabelle, Mme EBEL Claudine, Dr FREUND Jean-Noël, Pr MAUVIEUX Laurent, Dr TAVIAN Manuela, Dr VALLAT Laurent
Tous les auteurs :
Galland A, Gourain V, Habbas K, Güler Y, Martin E, Ebel C, Tavian M, Vallat L, Chenard MP, Mauvieux L, Freund JN, Duluc I, Domon-Dell C
Lien Pubmed
Résumé
The intestine-specific CDX2 homeobox gene, while being a tumor suppressor in the gut, is ectopically expressed in a large proportion of acute leukemia, and is associated with poor prognosis. Here, we report that turning on human CDX2 expression in the hematopoietic lineage of mice induces acute monoblastic leukemia, characterized by the decrease in erythroid and lymphoid cells at the benefit of immature monocytic and granulocytic cells. One of the highly stimulated genes in leukemic bone marrow cells was Bambi, an inhibitor of TGFβ signaling. The CDX2 protein was shown to bind to and activate the transcription of the human BAMBI promoter. Moreover, in a leukemic cell line established from CDX2-expressing mice, reducing the levels of CDX2 or Bambi stimulated the TGFβ-dependent expression of Cd11b, a marker of monocyte maturation. Taken together, this work demonstrates the strong oncogenic potential of the homeobox gene CDX2 in the hematopoietic lineage, in contrast with its physiological tumor suppressor activity exerted in the gut. It also reveals, through BAMBI and TGFβ signaling, the involvement of CDX2 in the perturbation of the interactions between leukemia cells and their microenvironment.
Mots clés
Acute monoblastic leukemia, BAMBI, ectopic expression, oncogene, tumor suppressor
Référence
Mol Oncol. 2021 May 6;: